Synthesis of 5-Hydrazino-2-cyclopentenone Derivatives by a Gold(I)-Catalyzed Cycloisomerization/Hetero-Diels–Alder/Ring-Opening Tandem Reaction of Enynyl Acetates

A highly efficient, one-pot synthesis of ring-fused 5-hydrazino-2-cyclopentenone derivatives is achieved by a gold(I)-catalyzed cycloisomerization/hetero-Diels–Alder/ring-opening tandem reaction of suitable enynyl acetates. By mixing the latter with a dialkylazodicarboxylate in the presence of a gold(I) catalyst, the 1,3-acyloxy migration/Nazarov cyclization process leads to dienyl acetate intermediates which are trapped by the heterodienophile present in situ. This provides strained intermediates which undergo highly regioselective ring opening by a retro aza-Michael reaction promoted by traces of water, eventually yielding the target compounds. Six- and seven-membered ring-fused cyclopentenones and piperidine- and tetrahydropyran-fused cyclopentenones bearing a pendant hydrazino functionality on a bridgehead carbon atom can be obtained in high yield (68–96%) by this approach.


■ INTRODUCTION
The 2-cyclopentenone ring is found in a variety of natural and biologically active compounds possessing a high structural diversity, many of which embed a ring-fused cyclopentenone moiety ( Figure 1). 1 The importance of the 2-cyclopentenones is further enhanced by a variety of chemical transformations that can be carried out on them, which explains their popularity not only as benchmark substrates for many chemical transformations but also as starting materials in the synthesis of more complex compounds. 2 Thus, due to their privileged nature, many methods have been developed to access diversely functionalized 2-cyclopentenones. 1−3 Among gold-mediated syntheses of 2-cyclopentenones, 1,2,4−8 those based on gold(I)-catalyzed cycloisomerization of propargyl alcohol derivatives have especially shown their efficacy in providing these valuable compounds. 1,2,9−15 We have recently contributed to this field with the synthesis of cyclopentenones fused with heterocyclic rings and their transformation into some natural compounds. 16−19 In his pioneering work on the gold-catalyzed cycloisomerization of enynyl esters to 2-cyclopentenones, 20 occurring via a 1,3acyloxy migration/Nazarov cyclization sequence, 21, 22 Zhang showed that the target compounds could be obtained through the hydrolysis of the cyclopentadienyl esters formed in the process when the reaction was carried out in "wet" dichloromethane. Under anhydrous conditions, instead, the cyclopentadienyl esters could be isolated in high yield. 15,20 We have recently reported on the synthesis of ring-fused, cyclopentadienyl hydrazine derivatives 4 (Scheme 1a) by a one-pot, cascade process entailing the cycloisomerization of suitably substituted propargyl vinyl ethers 1, 23−26 the hetero-Diels−Alder (HDA) reaction of cyclopentadiene intermediates 2 with a dialkylazodicarboxylate, and the acid-catalyzed ring opening of cycloadducts 3. 27 Since in the cycloisomerization of the corresponding propargyl esters 5 to 2-cyclopentenones, a cyclopentadienyl ester intermediate (6) is formed, 20 we were interested in evaluating whether the latter could react with a dialkylazodicarboxylate present in the reaction mixture to provide the corresponding 5-hydrazino-2-cyclopentenone derivative 8 28 bearing an N-substituted quaternary center, 29 through a selective C−N bond cleavage in cycloadduct 7 (Scheme 1b). In our previous work, we had demonstrated that the highly regioselective C 1 −N 8 bond cleavage occurs in the presence of either the gold(I) catalyst or traces of mineral acids. 27 In the analogous process carried out on propargyl esters 5, the stage which is set for the C−N cleavage after the cycloaddition (i.e., intermediate 7) is different (from 3), but we nonetheless hoped for a similarly regioselective C−N cleavage by a retro aza-Michael addition upon hydrolysis of the suitably positioned ester group.

■ RESULTS AND DISCUSSION
We carried out our first experiment by adding a solution of substrate 9 and diethyl azodicarboxylate (DEAD) (1 equiv) in CH 2 Cl 2 (distilled over CaH 2 ) to a solution of the IPrAuNTf 2 (2 mol %) catalyst in the same solvent (Table 1, entry 1). Monitoring the reaction by thin layer chromatography (TLC), we found that the conversion of the starting material into  reaction products was very slow as the former completely disappeared after 3 h. Gratifyingly, after an aqueous work-up, the 1 H NMR analysis of the crude reaction mixture revealed the presence of desired product 12 and the corresponding Nacetylated compound 13 in an approximately 5:1 ratio. 30 When we carried out the same reaction in undistilled CH 2 Cl 2 (entry 2), 31 the consumption of the starting material was still very slow, but after work-up, we recorded a very clean 1 H NMR spectrum with the signals of product 12 only, which was obtained in 86% yield after chromatography. Better results were obtained by using commercial t-Bu 3 PAuNTf 2 as the catalyst, the reaction being complete in 30 min and providing 12 in 94% yield (entry 3). We next carried out the same experiment in CH 2 Cl 2 freshly distilled from CaH 2 (entry 4). The starting material was consumed in 60 min, after which we stopped the reaction to obtain a 1:1 mixture of 12 and N-acetylated compound 13. In the next experiment (entry 5), we added water (0.3% v/v) to the reaction mixture, and similarly to the reaction carried out in undistilled CH 2 Cl 2 , the conversion of the starting material was complete in 35 min to provide compound 12 only (79% yield after chromatography).
The last two experiments, together with those reported in entries 1 and 2, show that water is essential to avoid the formation of the unwanted N-acetylated compound 13. Even the amount of water present in the commercial CH 2 Cl 2 that we used (without prior distillation over CaH 2 ) seems sufficient for this (entries 2 and 3). 31 Moreover, given the quantitative formation of product 12, the cycloaddition step must be much faster than hydrolysis of the intermediate acetate 6 which would instead lead to the corresponding unfunctionalized 2cyclopentenone. 20 Given the unpredictability of the water content in the commercial solvent, 32 we decided to add a measured amount of water to the reaction medium even using undistilled CH 2 Cl 2 (entry 6). These conditions did not affect the reaction rate (100% conversion in 30 min) and, expectedly, provided compound 12 only (95% yield after chromatography). These were the conditions which we later used in the evaluation of the scope of the reaction.
A series of experiments with catalysts obtained by premixing Ph 3 PAuCl (2 mol %) and different silver salts (entries 7−9) were also carried out in undistilled CH 2 Cl 2 to evaluate other catalytic systems, and in all cases, the starting material was quickly consumed (30 min) to form the target compound in very high yield (86−95%) after chromatography. These experiments show that the presence of residual silver cations in solution does not affect the reaction outcome. The experiment with AgSbF 6 as the silver salt was repeated in "wet" CH 2 Cl 2 providing the same results as in the undistilled solvent (entry 10). We also tried two other solvents: With toluene (undistilled) (entry 11), the consumption of the starting material was very slow, the starting material being consumed in 7 h, to nonetheless give 12 in 91% yield after chromatography. With dichloroethane (undistilled) (entry 12), the reaction was slow, too, reaching 83% conversion in 3 h.
A series of experiments were carried out with pivaloyl ester 10 (entries 13−16). The first experiment was carried out as usual in undistilled CH 2 Cl 2 , and after 23 min, we stopped the reaction to obtain cyclopentenone 12 in 90% yield after chromatography. We carried out, with this substrate, the reaction in sequence, too, by first mixing the catalyst and the substrate in CH 2 Cl 2 , and when the cycloisomerization was complete (10 min), we added DEAD. The TLC spot corresponding to the cycloisomerization product disappeared in 40 min, and after work-up, cyclopentenone 12 was obtained in 64% yield. Interestingly, with this ester as the substrate, the formation of the N-acylated byproduct was not observed when carrying out the reaction in anhydrous CH 2 Cl 2 , as after aqueous work-up, we observed the formation of 12 only (entries 15 and 16). Finally, we also tried benzoyl ester 11 as the substrate (entries 17 and 18), but the results were not as satisfactory as those with the previous esters. The cycloisomerization was complete in 10 min with both catalysts, with the formation, in the TLC plate, of a spot probably corresponding to a reaction intermediate which was completely converted into the product in about 1 h. However, 1 H NMR of the crude reaction mixture revealed the presence of two unidentified byproducts, and 12 was obtained in moderate yield (54−57%) after chromatography.
To have a clear picture of the reaction, we carried out two experiments with pivaloyl ester 10 in CD 2 Cl 2 (in NMR tubes), monitoring directly by 1 H NMR (Scheme 2).
We choose 10 to have simpler NMR spectra as this ester does not form the N-acylated product in mixture with 12. In the first experiment (see the Supporting Information), we added the substrate to the solution of the catalyst (2 mol % t-Bu 3 PAuNTf 2 ) to generate, in less than 1 min, diene 14, 30 and to this, we added an excess of DEAD (2 equiv) to initiate the cycloaddition step. The signals of diene 14 completely disappeared after 8 min, and at this point, the signals of two products, in a 3:1 ratio, were visible in the NMR spectrum, i.e., those that we could attribute to cycloadduct 15 (major), 30 as a single diastereomer, and to compound 17 (minor). 30 We then added D 2 O (0.3% v/v) which caused the quick transformation (2 min) of cycloadduct 15 into final product 12, whereas the conversion of minor product 17 into 12 was slower and required 10 min to be completed. After this time, only the signals of our target compound 12 were present in the 1 H NMR spectrum. In a similar experiment, we avoided the addition of deuterated water and found that the ratio between compounds 17 and 15 increased during the time, from 1:3 after 8 min to approximately 1.5:1 after 40 min. Thus, in the absence of water, cycloadduct 15 undergoes a slow cleavage of the C−N bond to generate cyclopentadienyl ester 17, and on the grounds of our previous work with propargyl vinyl ethers, 27 the ring-opening process leading to 17 could be promoted by the catalyst present, i.e., either by the cationic gold(I) or by the conjugated acid of its counterion (Tf 2 NH). As mentioned, with the substrate we used in the present experiments, we do not observe the formation of the N-acylated byproduct under anhydrous conditions. The formation of N-acetyl derivative 13 from 9 when working in the absence of water ( Table 1, entries 1 and 4) could derive from an intramolecular reaction on either 16 or 17 (when R = Me), whereas with the pivaloyl esters, N-acylation is not observed ( Table 1, entries 15−16) as it could be impeded by steric hindrance.
Based on the results of the above-mentioned experiments, we may infer that when the reaction is carried out under the optimized conditions, i.e., in the presence of water, the major pathway must involve the hydrolysis of the ester group directly in the cycloadduct 15 as soon as this is formed, which triggers the regioselective cleavage of the C 1 −N 8 bond by a retro aza-Michael addition driven by the formation of a conjugated system (path a, Scheme 2).
To gain insights into the role of the gold catalyst in the cycloaddition step and try to isolate the cycloadduct intermediate, we carried out an experiment on known diene 18 (Scheme 3). 15 By adding DEAD to a solution of 18 in anhydrous CH 2 Cl 2 and monitoring by TLC, we observed the complete disappearance of the starting material in 25 min, with the formation of cycloadduct 19, 30 of which we managed to record an 1 H NMR spectrum (which showed the presence of a single diastereomer) and an electrospray ionization-mass spectrometry spectrum by directly concentrating a small volume of the reaction mixture. 33 This experiment thus suggests that the gold(I) catalyst has no role in activating either the diene or the heterodienophile for the cycloaddition step. Instead, the addition of the gold catalyst to the solution of 19 caused the acid-catalyzed C−N ring cleavage to form 12 reasonably according to path b (Scheme 2) but in mixture with unidentified byproducts.
For the evaluation of the scope of the reaction, we screened a few heterodienophiles (DEAD, DIAD, and dibenzyl azodicarboxylate) and propargyl acetates bearing different substituents and distal carbo-and heterocyclic rings ( Table 2).
In most cases, we observed by TLC the quick disappearance (30 min) of the starting material with the concurrent formation of the desired products (obtained in 76−96% yield after chromatography) when the reaction was carried out in wet dichloromethane (DCM). In two cases only, the reaction was troublesome: (a) When using dibenzyl azodicarboxylate as the heterodienophile (with substrate 9), we noticed a fast decomposition of the heterodienophile during the reaction. This slowed the cycloaddition step, consequently allowing the hydrolysis of the intermediate acetate before the HDA process and lowering the yield of 29. (b) With phenyl-substituted substrate 22, because of a slower cycloaddition step, the hydrolysis of the intermediate acetate occurred in part, too, using both DEAD and diisopropyl azodicarboxylate (DIAD) as heterodienophiles.
We found that in these problematic cases, the reaction was best carried out in undistilled CH 2 Cl 2 without addition of water so that final products 29 (84%) and 34−35 (68−71%) could be obtained in good yield. With substrates bearing a seven-membered ring (25−27), the tandem reaction occurred as usual in about 30 min, and the target products (39−42) were obtained in very good yield (78−88%). In these cases, however, we observed the formation of a minor diastereomer  (12−15%) likely due to a lower facial selectivity in the HDA step, as previously observed with other dienophiles. 26 To obtain functionalized cyclopentenones fused with a piperidine and a tetrahydropyran ring, the reaction was carried out on substrates 23 and 24, respectively. With ester 23, the reaction was carried out with both DEAD and DIAD, providing products 36 and 37 in 76 and 79% yields, respectively. With this substrate, the initial gold-catalyzed rearrangement was slower (about 4 h) than that with the corresponding carbocyclic systems, whereas tetrahydropyran derivative 24 reacted much faster (both rearrangement and cycloaddition/C−N cleavage steps) and, again, with complete facial selectivity to provide 38 in 92% yield.
Finally, in view of the possible use of these cyclopentenones as intermediates in synthesis, we evaluated on two of these compounds (12 and 28, Scheme 4) the facial selectivity in reactions involving the α,β-unsaturated ketone moiety.
We choose a simple double bond reduction which was best carried out with both wet Pd/C (10%) as the catalyst in methanol and PtO 2 in acetic acid, quantitatively providing compounds 43 and 44, possessing three contiguous stereocenters, with very high facial selectivity. Nuclear Overhauser effect (NOE) studies 34 revealed that it is the N-protected hydrazine appendage that exerted the major hindrance as the addition of hydrogen occurred on the opposite side.

■ CONCLUSIONS
In conclusion, we have established a robust method for the synthesis of functionalized 2-cyclopentenones by trapping with dialkylazodicarboxylates the dienyl acetate intermediates which are formed in the gold(I)-catalyzed rearrangement of suitable propargyl acetates and the consequent highly regioselective ring opening of the HDA cycloadducts. The presence of the right amount of water is essential to promote the latter step which occurs via a retro aza-Michael reaction and to avoid the formation of the N-acylated byproduct. This tandem, one-pot process, which includes a sequence of four reactions (1,3acyloxy migration, Nazarov cyclization, HDA, and retro aza-Michael addition), provides in high yields (68−96%) unprecedented 5-hydrazino-2-cyclopentenone derivatives with an N-substituted quaternary center. Further elaboration of these products and the extension of the methodology to different classes of propargyl esters are currently being evaluated in our laboratories.  2 PdCl 2 (16 μmol, 1.6 mol %) were then added under a nitrogen atmosphere, and the reaction mixture was stirred at room temperature for 3 h. Water (25 mL) was then added, and the product was extracted with Et 2 O (3 × 20 mL). The combined organic extracts were washed with brine (50 mL) and dried over anhydrous K 2 CO 3 . After filtration and evaporation of the solvent, the crude reaction mixture was purified by flash chromatography affording the corresponding intermediate propargyl alcohol 49a − i, which was used immediately in the next step.
Structure assignment by NMR studies; proton NMR experiment carried out in CD 2 Cl 2 ; copies of 1 H and 13 C{ 1 H} NMR spectra for all new compounds; 1 H NMR spectra (enlarged view) of compound 12 recorded at variable temperatures (PDF) The Journal of Organic Chemistry pubs.acs.org/joc Article